This project evaluates the extent to which age-related changes in modulators of memory formation contribute to age-related changes in learning and memory in rats. We have found that injections of either epinephrine or glucose enhance memory in young and aged rats. Glucose also enhances memory in humans, including healthy elderly subjects and those with Alzheimer's disease. Such findings suggest that altered sympathetic - adrenal medullary functions might contribute to age-related cognitive changes. We recently obtained evidence that, in aged rats, epinephrine responses to stressors are markedly increased. However, in aged rats, epinephrine appears to lose its ability to increase blood glucose levels, suggesting that hepatic responses to epinephrine are impaired and may contribute to the cognitive deficits observed. The first set of experiments will determine the extent to which this is the case, with one likely outcome being that aging will provide a situation with which to demonstrate that increases in circulating glucose levels in response to epinephrine are not necessary for enhancement of memory by epinephrine. During the past grant period, we also found that direct microinjections of glucose into the medial septum or amygdala in young rats enhance performance in some tasks, with partial dissociation by task for the two brain regions. Our findings with direct brain injections suggest further that glucose interacts primarily with opiate agonists and that glucose effects on memory may be mediated by glucose metabolism through pyruvate. The second set of experiments uses direct injections of glucose and other drugs into the medial septum and amygdala, to determine whether either/both brain regions are sensitive to glucose injections in aged animals and to determine whether the actions of glucose identified in young rats are intact or impaired in old rats. Additional findings indicate that intraseptal injections of glucose may augment acetylcholine output in hippocampus and may be related to glucose effects on performance. A third set of experiments, using in vivo microdialysis, examines acetylcholine output in hippocampus under baseline (resting) conditions, conditions of behavioral testing, and after drug manipulations.